CRTH2 (Chemoattractant Receptor-homologous molecule expressed on T Helper 2 cells, also known as DP2) is a G protein coupled receptor expressed on the major pro-inflammatory cells: eosinophils, T-Helper 2 (TH2), and basophils. The receptor's endogenous ligand Prostaglandin D2 (PGD2) is derived from arachidonic acid by sequential actions of cyclooxygenase and PGD2 synthases. It has been reported that CRTH2, upon activation by PGD2, leads to a number of inflammatory responses, which includes eosinophil shape change and degranulation (Gervais et al., 2001, J. Allergy Clin. Immunol. 108, 982-988), basophil degranulation (Yoshimura-Uchiyama et al., 2004, Clin. Exp. Allergy 34, 1283-1290), TH2 cell cytokine secretion (Tanaka et al., 2004, Biochem. Biophys. Res. Commun. 316, 1009-1014) and TH2 cell chemotaxis (Gyles et al., 2006, Immunology 119, 362-368. CRTH2 genetic knock-out data has been reported. CRTH2 knock-out mice show a significant decrease in antigen-induced lung inflammation (Chevalier et al., 2005, J. Immunolo. 175, 2056-2060). In addition to the knock-out data, Ramatroban, a marketed drug in Japan, has established efficacy against allergic rhinitis and is currently in clinical trial for treatment of asthma. Although the compound was first developed as a thromboxan antagonist, recent studies show that Ramatroban is also a potent CRTH2 antagonist (Pettipher et al., 2007, Nature Reviews Drug Discovery 6, 313-325). It has been suggested that the efficacy of Ramatroban in asthmatic and allergic reactions is in part mediated through CRTH2. A compound closely related to Ramatroban, TM30089, has been shown to reduce the pathology of asthma in vivo (Uller et al., 2007, Respiratory Research 8: 16).
Blockage of CRTH2, therefore, presents an attractive approach to treat various PGD2-mediated inflammatory diseases. Among disorders in which PGD2 is implicated are respiratory disorders, skin disorders, and other disorders related to allergic reactions. These disorders include allergic asthma, allergic rhinitis, atopic dermatitis, chronic obstructive pulmonary disorder, osteoarthritis, rheumatoid arthritis and inflammatory bowel disease.
CRTH2 is also expressed in the central nervous system (Nagata et al., 2003 Prostaglandins, Leukotrienes and Essential Fatty Acids 69, 169-177). CRTH2 mRNA was detected in various brain regions including the thalamus, frontal cortex, pons, hippocampus, hypothalamus, and caudate/putamen (Marchese et al., 1999 Genomics 56, 12-21). Corradini et al (WO2005/102338) disclosed that small molecule antagonists of the CRTH2 receptor are efficacious in two rat models: the chronic constrictive injury model and Seltzer model. The data established a link between CRTH2 and pain.
Blockage of CRTH2, therefore, presents an attractive approach to treat various pain conditions such as neuropathic pain.